A5052997420- Parkinson's Disease Mechanisms and Treatments
- Cellular transport and secretion
- Lysosomal Storage Disorders Research
- Neurological diseases and metabolism
- Alzheimer's disease research and treatments
University of Dundee
2021-2025
MRC Protein Phosphorylation and Ubiquitylation Unit
2021-2023
Medical Research Council
2021
Abstract Heterozygous gain-of-kinase function variants in LRRK2 (leucine-rich repeat kinase 2) cause 1–2% of all cases Parkinson’s disease (PD) albeit with incomplete and age-dependent penetrance. All pathogenic mutations reside within the two catalytic domains LRRK2—either its domain (e.g. G2019S) modest effect or ROC-COR GTPase R1441G/H) large on activity. We have previously reported assays to interrogate pathway activity human bio-samples measuring phosphorylation endogenous substrate...
Leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of Rab GTPases that regulate receptor trafficking; activating mutations in LRRK2 are linked to Parkinsons disease. phosphorylation is transient event can be reversed by phosphatases, including PPM1H, acts on phosphoRab8A and phosphoRab10. Here we report phosphatome-wide siRNA screen identified PPM1M as phosphoRab12-preferring phosphatase also Upon knockout from cells or mice, displays selectivity for phosphoRab12. As shown...
Abstract Gain-of kinase function variants in LRRK2 (leucine-rich repeat 2) cause Parkinson’s disease (PD), albeit with incomplete and age-dependent penetrance, offering the prospect of disease-modifying treatment strategies via inhibition. phosphorylates a subgroup RabGTPases including Rab10 pathogenic mutations enhance LRRK2-mediated phosphorylation at Thr73. In this study we analyse dependent Thr73 human peripheral blood neutrophils isolated from 101 individuals using quantitative...